Genetic Testing
What are Genetic Tests?
You may be familiar with DNA tests marketed to adults in the U.S., such as Ancestry and 23andMe, that
give information about ancestry, general wellness, or physical traits. These tests and the companies that
provide them represent only a small portion of the total marketplace encompassing genetic or DNA
testing.
DNA testing and medical genetics is a rapidly-evolving field with ongoing ethical, logistical, and financial
challenges that are complicated. Abundant tests are available to provide information for assisting with
lifestyle choices, general health, and difficult medical decisions. The type of information can vary
dramatically between different tests, even from the same company.
Some of the DNA tests have undergone rigorous scrutiny and are approved by the U.S. Food and Drug
Administration (FDA), whereas others are not FDA-approved. Unlike anticancer drugs and other
pharmaceuticals that must pass established safety and efficacy standards, it is not required that genetic
or DNA tests receive FDA approval to be used by individuals and their health care providers. However,
among tests with medical implications for treatment, there needs to be a clinician involved to order the
test, receive, and interpret the results. Exceptions include ancestry and general wellness tests that
consumers can order directly.
Different Types of Genetic Testing
- Ancestry – Provides information on general features within your DNA. Examples include genetic matches to relatives, some inherited physical traits and certain characteristics.
- General wellness – Provides information about your general health within your DNA. Examples include whether you are allergic to certain things, the speed of your metabolism, and likely dietary preferences.
- Medical diagnosis – Determines whether or not a disease or condition is present. May also confirm a cancer diagnosis or establish features of the tumor, like its mutation rate.
- Predictions / Outcomes – Can provide some information about the risk of a future event. Examples include if a tumor is likely to metastasize to the lymph nodes or if cancer is likely to reoccur five years in the future.
- Pharmacogenomics – Determines whether a drug would work in an individual, due to their metabolism, or whether an individual is at high risk for significant side effects from a drug. Examples include whether a pain medication would provide relief for an individual or if a drug could elicit a life-threatening allergic reaction.
- Treatment decisions – Determines whether you may be eligible for a particular therapy or whether a clinical trial may be reasonable. Examples include whether immune check point inhibitors are working or if a clinical trial matches your tumor’s DNA mutations. Sometimes these are referred to as “companion diagnostics” which means that it is approved by the FDA to indicate its specific use with a particular drug.
There are many types of DNA or genetic tests. Here are some of the major categories that outline the
types of genetic tests available. Note that there is overlap between some categories among genetic
tests.
Landscape of Genetic and DNA Testing
as it Applies to Making Treatment Decisions
About Melanoma
The next section is designed to provide more information about the landscape of genetic or DNA testing
as it applies to making treatment decisions for patients diagnosed with melanoma, individuals with a
clinical suspicion of having inherited a cancer predisposition, and the population interested in melanoma
genetic testing. These tests assess the DNA we inherited in our normal cells or the DNA in our tumor
cells, or both, to better understand the tumor and fight the disease.
Most of the tests included on this page require a clinician or genetic counselor to assist with ordering
the test and interpreting the results collected. Some tests may not be eligible for reimbursement by
insurance or Medicare, and the decisions on coverage may change depending on the circumstances. As
an example, if a DNA test of a tumor sample is required for a patient with medical coverage to show the
tumor contains a BRAFV600E mutation and receive a physician-prescribed BRAF inhibitor, then it will
likely have some level of coverage. In contrast, if a patient wanted to have their ancestry analyzed to see
if they are related to certain individuals, this test would not be covered because it is not required for an
FDA-approved treatment.
Tests described below include: 1) FDA approved tests that evaluate tumors in order to make treatment
decisions and 2) other tests that are not FDA-approved, but may well provide information helpful for
patients and/or their close relatives. The list will start with the FDA-approved tests and is in alphabetical
order.
Melanoma Tumor DNA Evaluation
– FDA Approved Tests
These tests use a sample of your tumor tissue, extracted during a biopsy or tumor-resection surgery, to
provide information to your health care provider. The test results are used to optimize your treatment.
- cobas 4800 BRAF V600 Mutation Test – This test is an FDA-approved companion diagnostic. That means the test works in coordination with a specific drug or therapy.
The cobas test uses melanoma tumor tissue to detect the presence of BRAF mutations in that tum or DNA. A patient with a positive cobas test result is eligible for the drugs vemurafenib and cobimetinib. The presence of either V600E, V600D, and V600E2 indicates a mutation in BRAF is causing melanoma to grow rapidly. The drug vemurafenib can stop BRAF-driven growth.
Cobimetinib is necessary to prevent the cancer cell from quickly making vemurafenib
ineffective. - THXID-BRAF Kit – This test is an FDA-approved companion diagnostic. That means the test works in coordination with a specific drug or therapy.
The THXID-BRAF test uses melanoma tumor tissue to detect the presence of BRAF mutations in the tumor DNA. A patient with a positive THXID-BRAF test result is eligible for the drugs dabrafenib and trametinib. The presence of either V600E or V600K indicates a mutation in BRAF is causing melanoma to grow rapidly. The drug dabrafenib can stop BRAF-driven growth.Trametinib is necessary to prevent the cancer cell from quickly making dabrafenib ineffective. - FoundationOne CDx – This test is an FDA-approved companion diagnostic. That means the test works in coordination with a specific drug or therapy.
The FoundationOne CDx uses tumor tissue to detect the presence of BRAF mutations in the tumor DNA. A patient with melanoma and a positive FoundationOne CDx test result is eligible for a combination of the drugs atezolizumab, binimetinib, cobimetinib, dabrafenib, encorafenib, trametinib, or vemurafenib. It tests for the presence of BRAF V600E, V600K, and other V600 mutations.
In addition, the test assesses whether the tumor mutational burden is greater or equal to ten mutations per megabase or has microsatellite instability. If positive, this indicates the use of pembrolizumab for solid tumors. Furthermore, the test also detects mutations in other genes, like KRAS or HER2, that are relevant to treat cancers like colorectal or breast, respectively.
In total, the FoundationOne CDx test measures changes in 324 genes or parts of the tumor DNA. Although some of the genes indicate that a patient is eligible to receive an FDA-approved drug, not all of the genetic information provides a clear connection. For example, the test measures numerous changes within tumor DNA that have no currently available drug or therapy that can help. However, in the future, there could be clinical trials available for some of these changes. - FoundationOne Liquid CDx – This test is an FDA-approved companion diagnostic. That means the test works in coordination with a specific drug or therapy.
The FoundationOne CDx uses a blood sample to detect the presence of genes to indicate appropriate therapy. Specifically, blood plasma contains circulating cell-free DNA from the tumor. The test analyzes at least 300 genes, including blood tumor mutational burden and microsatellite instability-high which indicates the therapy needed. For solid tumors, it can detect NTRK1/2/3 fusions, which are common in spitzoid melanoma, that can be treated with the targeted therapy entrectinib. - MSK-IMPACT – The MSK-IMPACT is the Integrated Mutation Profiling of Actionable Cancer targets and available to patients treated at the Memorial Sloan Kettering Cancer Center. It was approved in 2017 by the FDA to detect DNA changes in an individual’s cancer, including melanoma, that would indicate and appropriate drug or clinical trial. It was the first academic tumor profiling test to receive approval.
The test collects two samples from patients: tumor tissue and normal tissue. DNA analysis of each tissue allows researchers to compare the DNA and determine what mutations have developed within the tumor. Treatment can then be targeted directly against the genetic and biological reasons driving the tumor growth. In addition, analyzing the normal tissue helps determine whether the patient inherited a genetic mutation that causes cancer.
In total, the test examines at least 505 genes, including those genes important for matching targeted therapy, such as BRAF. Since it is updated, the exact number of genes analyzed is likely to increase as more targeted therapeutics receive approval. A similar test. MSK-Impact Heme, is available for those patients diagnosed with blood cancers. - NYU-Langone Genome Pact – The PACT(Profiling of Actionable Cancer Targets) test is approved as a diagnostic test and qualitative assay by the FDA for solid tumors, such as melanoma. It is available to patients treated at the New York University Langone Health Cancer Center. The test compares a patient’s tumor tissue to their normal tissue to detect genetic alterations in their DNA. It detects alterations in the DNA of 607 genes.
Although it is not considered conclusive for diagnosis or prescriptive for labeled drug use, it is approved for use by health care providers to give information about tumor mutations. For patients with a cancer diagnosis, it can guide treatment decisions. An additional prospect for using the genetic information is that among some patients, it may detect a mutation that matches them to a current or future clinical trial. - TruSight Oncology Comprehensive – The diagnostic test kit is FDA approved and detects 517 genes from tumor tissue including BRAF, and RNA fusions in 24 genes. It also reports a tumor mutational burden score. The kit is intended for use by health care providers for multiple types of cancer, including melanoma. Results are intended to be used for guiding treatment decisions.
Additionally, this test is an FDA-approved companion diagnostic. That means the test works in coordination with a specific drug or therapy. For solid tumors, if NTRK1/2/3 fusions are detected then larotrectinib is indicated. Note: To perform this test, your doctor must have this kit, the machinery, and the expertise in-house; it likely will only be available at a major cancer center. - xT CDx – This test is FDA-approved for use with solid tumor tissue. It also has a companion diagnostic claim for patients diagnosed with colorectal cancer. The test uses tumor tissue to detect whether a normal or mutated KRAS and/or NRAS gene exists in the tumor DNA. Results may indicate whether a patient is eligible for either cetuximab or panitumumab.
The xT CDx evaluates 648 genes in solid tumors, including melanoma and BRAF. It also designates the status of microsatellite instability in the tumor tissue. Samples collected from the patient include tumor tissue, blood, and saliva. For patients that have been diagnosed with cancer, test results identify DNA mutations that can be used by healthcare providers to guide treatment decisions with the level of clinical significance in the report.
Other Genetic Tests to Guide Decisions for Patients with Melanoma – not FDA approved
The tests listed here are in alphabetical order and are not approved by the FDA. For this reason, they
may or may not be eligible for reimbursement and they do not provide information to work in
coordination with a specific drug or therapy.
The information generated by these tests should be evaluated by a licensed health care provider. Some
tests may help gauge your risk for inheriting melanoma or skin cancer, whereas other tests may help
suggest treatment recommendations or screening for cancer. If you’ve taken one of these tests and
have questions, call your clinician or contact AIM’s Ask an Expert with your follow-up questions.
- Altera Comprehensive Genomic Profiling – This test evaluates 440 genes in the tumor DNA, including BRAF for melanoma. The test also assesses microsatellite instability, tumor mutational burden, and PD-L1 expression. A clinician may consider these results when making treatment decisions. The report provides information on drugs that may be therapeutically relevant and clinical trials that are recruiting patients. A second test, called Signatera (see below), from this company may help monitor treatment efficacy. Both tests can be ordered by the care provider simultaneously using one tumor sample.
- CancerNext-Expanded –This test evaluates 76 genes in normal tissue to detect the presence of inherited genetics that increase an individual’s risk for melanoma, breast cancer, central nervous system tumors, colorectal cancer, gastric cancer, kidney cancer (also renal cell carcinoma), ovarian cancer, pancreatic cancer, prostate cancer, pheochromocytoma/paraganglioma, uterine cancer and cancer predisposition conditions.
The test is designed for individuals with a clinical suspicion of an inherited susceptibility to melanoma and other cancers. Inherited susceptibility is defined as when three or more close family members have melanoma or cancers of the brain, breast, colon, kidney, ovary, or uterus. The sample collection kit is ordered by a licensed care provider and interested individuals need to contact their clinicians for sample collection. - DecisionDx-Melanoma – This test evaluates 31 genes in the cutaneous (skin) melanoma tumor to predict the risk of cutaneous melanoma recurrence and the risk of sentinel lymph node positivity. Results of the genes expressed will generate a score for patients diagnosed with cutaneous melanoma. In collaboration with the clinical and pathologic features of the cutaneous melanoma, like thickness, ulceration, etc., the score provides an estimate to help guide decisions for treatment. For example, if the results suggest a patient has a very low risk score, they might decide, in consultation with their health care provider, to skip sentinel lymph node biopsy. A higher risk score that suggests recurrence might increase the frequency of clinic visits, prompt enrollment into a clinical trial, or necessitate advanced imaging.
- DecisionDx-UM – This test evaluates 15 genes in the uveal melanoma tumor to predict the risk of metastasis within five years. Results of the genes expressed will generate a risk score for patients diagnosed with uveal melanoma. Based on a high risk calculated by the test, a clinician may plan for enhanced surveillance of a patient after their primary eye surgery. A low risk may indicate that a clinician could safely be less aggressive in the post-surgical management plan. There are three risk categories: low, intermediate, and high, that indicate the time periods for follow-up imaging.
- Empower – This test evaluates 81 genes in normal tissue to detect the presence of inherited genetics that increase an individual’s risk for melanoma and 12 other types of cancer. More specifically, it is looking for mutations, if they exist, in specific genes that include BAP1, BRCA2, CDK4, CDKN2A, MITF, PTEN, TP53, and others. The Empower Hereditary Cancer Test is ordered by a health care provider. The patient provides either a blood or saliva sample for the test. Results may inform your health care provider about genetic issues that relate to managing your health. The test may also help guide decisions if it is performed after a cancer diagnosis.
- The Galleri test – This test evaluates a blood sample to look for DNA that is found in cancer cells, sometimes referred to as circulating tumor DNA (ctDNA) or cell free DNA (cfDNA). This type of DNA is not found normally in the bloodstream, so it indicates the presence of cancer cells. The Galleri test is considered a “screening test” for cancer, but it does not diagnose the disease.
The test looks for cancer cell DNA that is shed by a tumor. If it finds it, the results will indicate that a “cancer signal” was detected. The Galleri test predicts the tissue or organ that is likely associated with the signal. Then, a clinical diagnostic test, likely a biopsy, would be necessary to find the tumor, confirm the test results, and diagnose cancer.
If no cancer cell DNA is found in the blood, the results will indicate that “no cancer signal” was detected. A negative result does not definitively mean that an individual has no cancer. Cancer could be located elsewhere in the body, like the brain, which does not shed DNA into circulation, or the cancer may not yet be at the stage to shed DNA into circulation. The test is recommended for recommended for individuals over 50 years and at an elevated risk for cancer. - Hereditary Melanoma and Skin Cancer Panel – This test evaluates 19 genes in normal tissue to detect the presence of inherited genetics that increase an individual’s risk for melanoma and basal cell carcinoma. More specifically, it is looking for mutations, if they exist, in specific genes which include BAP1, BRCA2, CDKN2A, MITF, POT1, and others.
It is designed for individuals with a clinical suspicion of an inherited susceptibility to melanoma and other skin cancers. The results may indicate whether an individual has inherited familial atypical multiple mole melanoma syndrome, Gorlin syndrome, Li-Fraumeni syndrome, and others. The sample collection kit is ordered by a licensed care provider and sent to the individual. - Invitae Multi-Cancer Panel – This test evaluates 70 genes in normal tissue to detect the presence of inherited genetics that increase an individual’s risk for melanoma, basal cell carcinoma, or other types of cancer. The test includes melanoma susceptibility genes such as BAP1, BRCA2, CDK4, MITF, POT1, and others.
It can be ordered online through a telehealth appointment with a clinician. After a pre-test consultation, the genetic test is shipped to the individual who provides a saliva sample and sends it back to the company. Results are shared with the individual through a genetic counselor. These include confirming a diagnosis, predicting disease, or facilitating early detection. Note that genetic counseling through Genome Medical is mandatory to purchase this test, but is available through a self-pay option, currently priced at $199, or insurance. The Invitae genetic results can be shared with your local health care provider to manage your health. - Invitae Personalized Cancer Monitoring: Baseline and Monitoring Tests – These two tests are used to measure circulating tumor DNA or ctDNA. The baseline test requires a tumor sample and two blood samples. Using these materials, the baseline test will identify pieces of the patient’s tumor that are specific to their melanoma. This information will be used later in the second test.
The monitoring test can be ordered only after the baseline test has been completed. It will look for the presence of the specific pieces identified from the patient’s tumor found in the baseline test. Using a new blood sample from the patient, ctDNA can be detected, if it is present. Detecting ctDNA could indicate residual disease. In theory, the test could also be used to monitor the effectiveness of anti-cancer treatment to help determine whether the current treatment is working or whether a new treatment approach is needed. - MelaNodal Predict – This test evaluates eight genes to predict sentinel lymph node metastasis in patients who are eligible for sentinel lymph node biopsy. More specifically, the test is evaluating the expression of MLANA, GDF15, CXCL8, LOXL4, TGFBR1, ITGB3, PLAT, and SERPINE2. The test requires a sample of the primary melanoma. Per the company, patients who have test results indicating “low risk” have a 5-year melanoma specific-free survival rate of 98% and may be able to forego the invasive procedure because they are unlikely to have tumor in their lymph nodes. Per the company, patients who have test results indicating “high risk” have a 5-year melanoma specific-free survival rate of 88%, and should be considered for the invasive procedure because they have a higher probability of sentinel lymph node metastasis. Results and treatment considerations should be discussed with your healthcare provider.
- Melanoma Comprehensive Panel – This test evaluates 14 genes in normal tissue to detect the presence of inherited genetics that increase an individual’s risk for melanoma. More specifically, it is looking for mutations, if they exist, in certain genes which include BAP1, BRCA2, CDK4, CDKN2A, MITF, POT1, TP53, and others. Individuals that have certain “red flags” are the targets for this test, which include having cancer before the age of 50 years, having more than one primary cancer, and having multiple people diagnosed with cancer within a family. The individual provides either a blood sample, a buccal swab, or saliva for the test. Results may inform your health care provider about genetic issues that relate to managing your health.
- Melanoma Panel – This test evaluates 10 genes in normal tissue to detect the presence of inherited genetics that increase an individual’s risk for melanoma. More specifically, it is looking for mutations, if they exist, in certain genes which include BAP1, BRCA2, CDK4, CDKN2A, MITF, POT1, TP53, and others. Individuals recommended for this test have multiple family members with melanoma. In addition, it is recommended for members of families with melanoma that may have other cancers, especially one or more family members with pancreatic cancer. Even though it is called “melanoma panel,” the test is designed to detect inherited genes – not cancer. It is not used to decide treatment.
- MyPath Melanoma – This test evaluates 23 genes in cutaneous (skin) melanocytic lesions to determine whether the sample is benign, intermediate or malignant. The genes that are evaluated include several involved in cancer cell signaling and tumor immune response, and one expressed abnormally by melanoma. Results can help increase the clarity of pathology reports, improve confidence in a difficult diagnosis, and help make decisions about management. A primary tissue biopsy or excision sample is required for the test. A MyPath Melanoma score is calculated from the genes expressed.
- MyRisk Hereditary Cancer Test – This test evaluates at least 50 genes in normal tissue to provide an inherited level of risk for developing 11 types of cancers, including melanoma. For example, the test can detect mutations within normal tissue that indicates whether your DNA puts you at “high risk” or an “elevated risk” for certain cancers. More specifically, if the test detects a certain mutation in the BRCA2 gene, this indicates an increase cancer risk for melanoma, breast cancer, ovarian cancer, and pancreatic cancer. The report also includes management options to monitor health status and reduce the risk of a late diagnosis.
- PGDx elio tissue complete – The Personal Genome Diagnostics’ PDGx elio tissue complete is an FDA cleared kit designed to provide information about the tumor’s genetics. It measures 505 genes and is applicable for DNA from 35 types of solid tumors, including melanoma. The tumor mutation burden is also measured by this kit. FDA cleared is not the same as FDA approved. Note: To perform this test, your doctor must have this kit, the machinery, and the expertise in-house; it likely will only be available at a major cancer center.
- Precise Tumor – This test evaluates 523 gene variants and 56 RNA variants in the tumor tissue to help guide treatment decisions. It also evaluates microsatellite instability, tumor mutational burden, and has an option to measure PD-L1 expression. The test includes BRAF in the panel but has many genes that apply to other types of cancers, rather than solely melanoma. The test is requested by the health care provider and requires a tumor sample. Results are reported to the health care provider to be shared with the patient for therapy decisions.
- The Riskguard test – This test evaluates 56 genes in normal tissue to provide an inherited level of risk for developing 10 types of common cancers, including melanoma and other skin cancers. More specifically, it is looking for mutations, if they exist, in certain genes which include BAP1, BRCA2, CDK4, CDKN2A, MITF, PTCH1, PTEN, and others. The Riskguard test can be ordered by your health care provider. A specimen collection kit can then be shipped to your home or clinician’s office to collect either blood or saliva. Results are reported to the health care provider and available to the individual online. Genetic counselors are also available.
- Signatera – This is a prognostic test, which means that it provides information about the chance of recurrence, by evaluating whether molecular residual disease is present in a patient diagnosed with melanoma. The test is designed to detect the presence of circulating tumor DNA (ctDNA) in blood, which indicates cancer. Signatera is also prognostic for disease-free survival and overall survival. The goal is to identify treated patients who are at a high risk for tumor recurrence. It can also be used to track disease dynamics over time. The test is covered by Medicare for certain patients with cancer for immunotherapy efficacy monitoring when the drug may be working but imaging does not reflect it.